The Purine Research Society

What We Learn About Metabolic Disease Will Benefit Each and
Every One of Us

The Purine Research Society was formed in 1986 by parents
of children with autism who excrete too much uric acid in their urine. Each family contributed a
significant amount of money to fund M.D./Ph.D. researchers to
find out why their children with autism were excreting excess
uric acid, the end product of purines. Several researchers have
studied the problem, and there continues to be significant
progress. One of the accomplishments of the Society has been to
produce a pamphlet explaining metabolic diseases in general and
purine metabolic diseases in autism, as well as other diseases
with excess uric acid, such as gout.

WHY WE AREN'T WHAT WE EAT

Every day of our lives, starting with the day we were
born, we have been consuming food. We start with milk and
gradually progress to cereals, fruits and vegetables, and
meats. As we grow older, we may develop a preference for
chocolate, salsa, or caviar. Indeed, the ability to
satisfy our nutritional needs with a wide variety of
foodstuffs is a distinct advantage. And yet, the skin,
bones, hair, and muscle which make up our bodies are
obviously very different from these foodstuffs. How is it
that we are able to convert these foods into the
materials which compose our bodies and use them to
produce the energy we need to survive and function?

The excessive uric acid production during the childhood of children with autism greatly diminishes or disappears at puberty.

THE BODY'S ANSWER --- METABOLISM

Metabolism is the body's answer to this
question. Our bodies are like individual chemical factories. In
the cells that make up our bodies, thousands of different
chemical reactions which keep us alive are constantly taking
place. Together, these reactions make up our metabolism,
converting the wide variety of chemical compounds that we consume
into the chemical compounds that we need.

Each chemical reaction is helped along by a specific protein
catalyst called an enzyme. As catalysts,
enzymes increase the rate at which specific chemical reactions
take place. But in the process, the enzyme itself remains
unaltered. Enzyme catalysts are amazingly specific and efficient.
Enzymes catalyze thousands of reactions at the same time, in the
same place (a cell in your body), and with virtually a 100%
yield. Compare that with a chemist attempting to synthesize a
particular compound in the laboratory. The chemist is limited to
producing no more than one compound at a time in the same place
(the test tube), and with a yield which is usually considerably
less than 100%.

When our bodies convert a typical food molecule such as
sucrose (sugar) into a very different molecule, such as a fat
molecule for energy storage, many small steps are required. Each
step is catalyzed by a specific enzyme. The sequence of steps by
which one molecule is converted to another is known as a metabolicpathway.

THE IMPORTANCE OF GENETICS

How do our bodies produce so many individual, unique enzymes?
The explanation lies in the study of genetics,
the scientific study of heredity.

The structure of each enzyme is determined by a specific gene,
part of the hereditary material which exists in every cell in our
bodies. In most of us, our genes work to produce enzymes that
function flawlessly. But in one out of every 100 live births, a
defective enzyme gene occurs, resulting in a partially or
completely non-functioning enzyme. (In rare cases, a defective
gene results in an enzyme with too much activity.) Then, like
traffic backed up behind a washed-out bridge, the molecule
normally converted by that enzyme (the substrate)
builds up; the molecule normally produced by that enzyme (the product)
becomes scarce. Two important consequences result:

the accumulated substrate may be toxic to us; or

the deficiency of the product may handicap our ability to
survive and function.

THE BAD NEWS --- METABOLIC DISEASES

Distress to the body resulting from the production of too much
of a toxic substance or too little of an essential one is
referred to as a metabolicdisease.

Metabolic diseases are inherited and are present from birth,
although the disease may first manifest itself at any age. The
resultant metabolic diseases, which can occur in any area of
human metabolism, could affect our lives or the life of someone
close to us. Most of us have heard of these more familiar
metabolic diseases:

SickleCellAnemia,
caused by a defect in the protein which carries oxygen;

CysticFibrosis,
resulting from a defect in the enzyme that transports
salt. This in turn can be treated throughout a lifespan with a cpap ventilation mask to support and assit recovery; and

LactoseIntolerance,
caused by a defect in the enzyme which digests the sugar
(lactose) in milk.

Some other diseases are obviously inherited metabolic
disorders, but researchers have not yet identified the defective
enzyme.

WHERE DO PURINES FIT IN?

The class of chemical compounds known as purines
was first encountered in a waste product of metabolism known as uricacid,
which causes gout. "Purine," coined by chemist Emil
Fischer in the 19th century, comes from the Latin PURUS
(pure, clean) and New Latin URICUS (uric acid,
from urine). All purines share the basic nine-membered ring
structure shown below.

Figure 1. The Purine Nucleus. All naturally
occurring purinecompounds are
a variation on this structure.

As the informationmolecules
in genes, they are used in the process of converting
genes to proteins.

As energytransducers,
they convert the energy produced by the oxidation of food
molecules to a form which the cell can use to satisfy its
energy needs.

In cellularsignalingprocesses,
such as nerve conduction and muscle contraction, they act
as messengers.

As a disposalmechanism,
they rid cells of excess nitrogen.

As antioxidants, they protect the cell
from cancer-causing agents.

RECOGNIZING PURINE METABOLIC DISEASES

When we consider the many different roles purines play in our
metabolism, it is not surprising that the diseases of purine
metabolism are as varied, ranging from asymptomatic conditions,
which are only discovered accidentally, to disorders with severe
neurological abnormalities, which are ultimately fatal. As with
other metabolic diseases, each disorder is caused by a defectivegene
which results in an enzyme with too little or too much
catalytic activity. The numbered enzymes referred to
below are shown in Figure 2. Purine metabolic diseases include:

Gout. The most common defect of purine metabolism is
one of the oldest known metabolic diseases. Gout was known to the
ancient Egyptians, and was extensively studied by the Roman
physician Galen (A.D. 131-200). We now know that gout is caused
by overproduction of uric acid, with a consequent depositing of
uric acid crystals in the joints. Several different enzyme
defects cause gout, notably deficiency of HPRT (enzyme 21). Gout
can be treated successfully by limiting purines in the diet and
by using drugs which inhibit xanthine oxidase (enzyme 27) and,
thereby, the production of uric acid.

Lesch-Nyhan Syndrome. One of the better known diseases
of purine metabolism is caused by a deficiency of HPRT (enzyme
21). Symptoms include very severe gout, poor muscular control
(patients are wheelchair-bound), and moderate mental retardation.
The most unusual feature of Lesch-Nyhan syndrome is compulsive
self-injury, including chewing of the tongue, lips, and fingers.
Targeted treatment of symptoms is available, but overall therapy remains unknown.

Adenosine Deaminase (ADA) and Purine Nucleoside
Phosphorylase (PNP) Deficiency. A deficiency of either ADA
(enzyme 24) or PNP (enzyme 25) causes a moderate to complete lack
of immune function. Affected children cannot survive outside a
sterile environment. They may also have moderate neurological
problems, including partial paralysis of the limbs. When a
compatible donor can be found, bone marrow transplant is an
effective treatment. Recently, some experimental therapies have
also been successful.

Adenylosuccinate Lyase Deficiency. A deficiency of
enzymes 9 and 12 results in mental retardation, seizures, and
autistic behavior. No successful treatment has been established
to date.

Myoadenylate Deaminase Deficiency. A deficiency of
enzyme 13 impairs the ability of muscles to regulate energy
during exercise. The most prominent symptoms are muscle fatigue
and cramps after normal activities, such as climbing stairs.
Several experimental therapies appear to be helpful.

5' Nucleotidase Defect. The most recently described and
most unusual defect of purine metabolism is caused by excessive
activity of the enzyme 5' nucleotidase (enzyme 23). Symptoms
include constant infections, seizures, skin rashes, and very
unusual behavior, characterized by extreme hyperactivity, short
attention span, lack of speech, and poor social interaction. This
disease appears to be fully treatable by diets which restore the
compounds that are consumed by the excessive enzyme activity.

Phosphoribosyl Pyrophosphate (PRPP) Synthetase Defects.
Two distinct defects are associated with enzyme 1. Enzyme
deficiency results in convulsions, autistic behavior, anemia, and
severe mental retardation. Excessive enzyme activity causes gout,
along with various neurological symptoms, such as deafness. Aside
from the treatment of gout, no treatment for the symptoms of
these diseases is available at this time.

Xanthinuria and Adenine Phosphoribosyltransferase (APRT)
Deficiency. A deficiency of either xanthine oxidase (enzyme
27) or APRT (enzyme 20) causes accumulation of xanthine or 2,8
dihydroxyadenine, respectively. Often this causes no symptoms at
all, and patients are discovered accidentally during some other
kind of medical test. In other cases, these compounds accumulate
and crystallize in the joints, causing a gout-like condition. No
effective treatment is known, though reduction in dietary purines
is often helpful.

THE GOOD NEWS --- UNLOCKING THE SECRETS OF PURINE
METABOLISM

Historically, research in purine metabolism has always been at
the forefront of medical investigation. Owing to the importance
of purines in metabolism, this research has consistently led to
significant advances in other areas. Among the most noteworthy:

1942 In testing synthetic purine compounds to inhibit
the growth of bacteria, Hitchings and Elion hit on the "antimetabolite"
concept. According to this concept, a synthetic compound which
sticks to an enzyme and prevents reaction with a natural
substrate can be used to selectively "turn off" an
enzyme. For their pioneering work, these two researchers were
awarded the Nobel Prize in 1988. This concept has been employed
in the design of many modern drugs, including those for the
treatment of cancer, AIDS, and bacterial infections.

1967 The first psychiatric abnormality which could be
attributed to a specific enzyme defect, Lesch-Nyhan
syndrome, was described. Although the extent to which
genes can influence behavior is still very controversial, this
was the first demonstration that a gene defect could cause a
specific behavior (i.e., compulsive self-injury). More recently,
researchers have tentatively identified genes linked to
depression, alcoholism, and schizophrenia in some families.

1980 The first human disease shown to be caused by excessive
(rather than deficient) enzyme activity, PRPP synthetase
superactivity, was described. Discovery of the mechanism
through which excessive enzyme activity causes a disease has led
to greater understanding of metabolic regulation.

1982 The first gene for a human enzyme, HPRT
(enzyme 21), was artificially produced in the laboratory, or
cloned. Today, more than 200 human enzyme genes have been cloned,
helping us not only to understand the precise molecular events
which cause genetic diseases, but also to detect carriers of
these disorders.

1992 The first successful use of genetherapy,
the insertion of a normal, functioning gene into cells which
contain abnormal, nonfunctioning genes, was achieved with adenosinedeaminase.
Patients previously confined to germ-free enclosures were now
able to venture outdoors. This is perhaps the most important
advance in medical research in decades, and may produce
treatments for everything from cancer to baldness.

THE GOAL OF THE PURINE RESEARCH SOCIETY

The Purine Research Society (PRS) was founded to support
research aimed at furnishing a biochemicalexplanation
for the mechanism through which enzyme defects result in clinical
diseases. Researchers believe this to be the most direct route to
providing diagnostic capabilities and identifying potentially
useful treatments.

The Metabolic Basis of Purine Autism

Three surveys have shown that between 11% to 28% of children with autism excrete excessive uric acid during their childhood years, a phenomenon that diminishes or disappears with the onset of puberty. There also are a number of single case reports of hyperuricosuria in children with autism in the literature. In spite of extensive research, how hyperuricosuria relates to autistic symptoms has never been established. One study suggested that this temporary phenomenon may be due to a defect in purine nucleotide interconversion, as shown by an abnormal ratio of adenine to guanine nucleotides. Further research is needed to determine the meaning of why this secondary lab abnormality is found in several types of autism.

The Neurochemistry of 5' Nucleotidase Superactivity

A single study has described four unrelated children with a developmental disorder with low levels of uric acid in the urine due to increased enzyme activity related to pyrimidine salvage. A double blind study indicated that the children’s symptoms could be reversed by uridine. However the current diagnostic test is expensive and labor-intensive, not suitable for screening. Duplication of this study and development of an inexpensive screening test is needed.

Purine Production and Brain Development in Lesch-Nyhan
Syndrome

One of the better known diseases of purine metabolism is still without effective treatment for self-mutilation. This is the Lesch-Nyhan syndrome, an X-linked recessive disorder caused by a deficiency in a purine salvage enzyme. Although more than 300 disease-associated mutations in the HPRT1 gene have been identified, at present treatments remain merely symptomatic.

Adenylosuccinate Lyase (ADSL) Deficiency

Adenylosuccinate Lyase deficiency is an autosomal recessive disorder of de novo purine synthesis which results in accumulation of succinylpurines in body fluids. Half of these children have autistic features; 80% have seizures. Currently there is no established therapy, but trials of research drugs are underway.

FROM AUTISM IN CHILDREN TO GOUT IN ADULTS, RESEARCH ON PURINE
DISEASES IS LEADING TO EVENTUAL TREATMENTS.